As of 1992, more than ten million people in the United States of America suffer from diabetes (an increased level of glucose in the blood) and hypoglycemia (a reduced level of glucose in the blood). Individuals afflicted with either disease in a severe form typically perform an invasive blood glucose level analysis four or more times a day.
Invasive techniques require withdrawal of a blood sample from the patient each time an analysis is to be performed. An accurate laboratory blood analysis requires withdrawing from 5 to 10 ml of blood and analyzing it using a laboratory instrument designed for performing such a biochemical analysis. However, the results of the test often are not available for several hours, and sometimes days. In addition, the instruments necessary to perform such an analysis are expensive and require that the blood samples be taken and analyzed by trained technicians.
Another invasive technique, referred to as a "finger poke" or a "finger stick" uses an integrated, self-contained instrument that evaluates a much smaller blood sample (approximately 0.25 ml). The small blood sample is obtained by puncturing a finger with a small lancet. The sample is then placed on a chemically treated carrier and inserted into the instrument. The finger poke devices normally provide the glucose concentration results in a few moments. However, they are still quite costly for private use, i.e., in the range of several thousand dollars.
More recently, portable finger poke instruments have become available which require the use of single use, disposable, chemically treated carrier "strips." Although the portable instruments have a relatively low cost (about $100 to $300), the cumulative cost to diabetics for the normal supply of disposable carrier "strips" is considerable.
Invasive techniques for glucose analysis are problematic and suffer from poor patient compliance. Many people who would benefit from knowing their glucose concentration are reluctant to have blood withdrawn by a finger poke or a hypodermic needle or have a generalized fear of invasive medical procedures. Still others suffer anxiety in connection with the sampling and worry about the discomfort (pain) and possibility of infection. Another problem is that frequent invasive glucose testing uses up convenient sample sites and complicates further testing until the used convenient sites heal.
Non-invasive methods for measuring blood constituents, including glucose have been described. However, to date none of these techniques has resulted in a commercially useful instrument. The non-invasive monitoring methods are roughly divided into measurements based on either the intensity of light being transmitted through or reflected from the tissue, or the phase shift of modulated light transmitted through the tissue (the "phase-sensitive" measurement).
When light is transmitted through perfused tissue in vivo, e.g., through a patient's finger, it is differently absorbed by the various components illuminated, namely blood, with its many constituent parts, tissue (including protein, fat, water, cholesterol, etc.), cartilage, and bone. The different components thus form an absorption spectrum for each wavelength. The total absorption of a given wavelength of light by all of the components is called "real absorption" and the absorption spectrum may vary for different wavelengths.
The known intensity sensing methods for measuring the level of a blood constituent, including glucose, are based on measuring a real absorption spectrum for blood perfused tissue at two or more different wavelengths, and subtracting therefrom the statistical absorption spectra for each of the various blood components, except for the one component being measured. It is assumed that after such subtraction, the remainder is a real spectrum of the constituent to be measured.
Rosenthal et al. U.S. Pat. No. 5,086,229 refers to such a non-invasive, near-infrared quantitative analysis instrument for measuring blood glucose. The instrument contains a plurality of near-infrared laser sources having different wavelengths of emission and one or a plurality of photodetectors. A blood-containing part, e.g., a finger, is placed between the laser sources and photodetectors. The light sources are illuminated and the wavelengths then transmitted through the blood-containing part are detected. The real absorption spectrums obtained from the photodetector signals are compared with individual statistical absorption spectra of each constituent, which are stored in the memory of the instrument. A glucose level is derived from the comparison.
The intensity measuring instruments, including the Rosenthal instrument, suffer from the following disadvantages. First, because they measure intensity, the noise level of the measured signal is affected by components of the tissue other than blood, and variations in conditions such as background light, tissue temperature, ambient temperature, and the amplitude of the laser source. This results in a poor signal-to-noise ratio. Even the use of the latest low-noise electronics would not substantially improve this ratio.
Second, because the subtraction technique is based on statistically derived absorption data for each individual constituent, the results obtained are of necessity statistical. However, the differences between the actual glucose level in blood and the results of statistical measurements may be substantial and significant. In this regard, the absorption due to the glucose concentration is very small compared to other components such that statistical errors may be a greater component of the determined value than the actual glucose component.
The non-invasive phase sensitive measurement methods possess significantly higher sensitivity and a much higher signal-to-noise ratio than intensity-measurement methods. The higher sensitivity is the consequence of the noise sources affecting the amplitude, but not the phase, of a signal.
In phase sensitive techniques, an instrument compares a known reference signal, e.g., a sine wave, with a measurement signal that has been passed through the tissue. The measurement signal will have a time delay (phase shift) relative to the reference signal because of various factors, e.g., a fluorescence time delay, etc. Concentrations of blood constituents then may be obtained from a measurement of the time delay (phase shift).
Cote et al., "Noninvasive Optical Polarimetric Glucose Sensing Using A True Phase Measurement Technique," IEEE Transactions of Biomedical Engineering, Vol. 39, No. 7, July 1992, pp. 752-756 ("Cote") refers to passing linearly-polarized light through the anterior chamber of an excised human eye and determining the glucose level of the aqueous eye humor based on the phase shift between the reference signal and the measurement signal that was converted by the glucose. A helium-neon laser beam, coupled through a rotating linear polarizer along with two stationary linear polarizers and two detectors, is used to produce reference and signal outputs. The polarizer was rotated by means of a synchronous electric motor. The amplitudes of these outputs varied sinusoidally with a frequency twice that of the angular velocity of the rotating polarizer. The phase difference of the outputs would be proportional to the rotation of the linear polarization vector passing through the anterior chamber of the eye.
One problem with the Cote apparatus is that it uses a synchronous motor which generates mechanical vibrations which cannot exceed, e.g., 200 Hz. Therefore, the frequency of rotation of the motor falls into the frequency range (1 Hz to 600 Hz) of mechanical vibrations produced by different sources, interferes with those mechanical vibrations, and produces high measurement noise. Consequently, the Cote technique can be implemented only under laboratory conditions where mechanical vibrations can be isolated, and is unsuitable for application in the form of a portable instrument for personal use.
Another problem with the Cote measurement system is that it is based on passing the light through the human eye. It is thus inconvenient for practical self-administration of the test. More important, however, is that the eye is subject to involuntary movements (such as microsaccadic movements) which fall into the same frequency range as the rotating frequency of the driving motor of the system and have amplitudes of 1 to 3 min of arc. Should the apparatus be used in vivo, such involuntary eye movements would lead to interference with the measurement signals and would markedly increase the measurement noise.
Still another problem with the Cote system is that the axis of the synchronous motor can be fixed with respect to the direction of propagation of optical signals with an accuracy not exceeding several minutes of arc. This means that using the device requires that a calibration be carried out in real time.
Thus, there is a continuing need for improved non-invasive analytical instruments and methods that would provide essentially the same accuracy as conventional invasive blood glucose tests. There also is a need for non-invasive, low-cost methods and instruments for the measurement of glucose levels in diabetic or hypoglycemic patients. There also is a need for a durable, cost-effective, and environmentally conscious nondisposable apparatus for measuring blood glucose.
The applicant has developed a method and apparatus for non-invasive measurement of blood glucose concentration which is described in said parent U.S. patent application Ser. No. 08/071,321 now pending and commonly assigned, the disclosure of which is incorporated herein by reference in its entirety. These methods and apparatus are based on producing a phase-modulated laser beam via a polarizing frequency shifter, measuring a phase difference introduced, e.g., by a finger or a ear lobule of a subject, measuring phase difference between a reference signal and a probe signal, and processing the obtained data which are then presented as blood glucose concentration.
Although the inventions described in said parent U.S. Ser. No. 08/071,321 make it possible to produce high-resolution non-invasive optical measurements of the blood glucose concentration, and thus overcome the deficiencies of the prior art, the apparatus disclosed uses a polarizing frequency shifter which is based on the use of bulk optics (crystal optics) which is expensive. In addition, an apparatus which contains a bulk-optic type polarizing frequency shifter cannot be produced in small dimensions because its polarizing frequency shifter cannot be manufactured in an integrated-optic implementation. The present invention is directed to an improvement of the methods and apparatus disclosed in the aforementioned U.S. patent application.